One of the most important concepts in TIVA is opioid bioequivalence.
Since the opioid has a synergistic effect with propofol, it allows a lower propofol concentration to be used. This is similar to MAC reduction of inhaled anaesthetics by opioids.
The above diagram shows the usual dose response curve. Note how steep the curve is initially:
- This means that a relatively low concentration of opioid will significantly reduce the anaesthetic concentration
- The 50% anaesthetic reduction point lies on the steepest part of the curve. This means that it is very difficult to exactly measure the opioid concentration for 50% reduction
- At an opioid concentration of 3 times this 50% value, most of the anaesthetic sparing effect is achieved, and further increases in opioid concentration has a much smaller effect
For example, let us say that a concentration of 1ng/mL of fentanyl can reduce the MAC by 50%.
And for alfentanil, it is 30 ng/mL. And a concentration of 1.37 ng/mL of remifentanil also reduces MAC by 50%.
This implies that a fentanyl concentration of 3ng/mL, an alfentanil concentration of 90ng/mL, and a remifentanil concentration of 4ng/mL will achieve near maximal effect.
These numbers are approximate and for illustrative purposes only.
The above table illustrates the doses to achieve the aforementioned concentrations in a hypothetical person.
Notice that:
- To achieve fentanyl at 3ng/mL, a bolus of 150mcg followed by a steadily decreasing infusion ranging from 150-250mcg/hr over 4 hours
- To achieve alfentanil at 90ng/mL, a bolus of 1mg followed by a steadily decreasing infusion ranging from 2000-2500mcg/hr over 4 hours
- For remifentanil at 4ng/mL, a simple small bolus and constant rate infusion over the entire time period
Also note the time taken for the effect site concentration to drop by half after 1 to 4 hours for the different opioids:
- For fentanyl, starts at about 25 minutes after the first hour, but drastically increases as infusion time increases
- For alfentanil, a much more gradual increase from 23-30 minutes
- For remifentanil, the time to drop 50% appears to be independent of infusion duration
This may be familiar to those who have heard of the term context-sensitive half time (CSHT).
Note that this is different to the often heard term “half-life”, e.g. the half-life of drug XYZ is 4 hours. This “half life” is usually measured after single dosing, and is not particularly useful in our situations. This is because there is not one fixed “half-life” for a drug. It changes with dose, dosing frequency, and duration of treatment. It is usually a combination of elimination and redistribution all mixed into a single number.
The CSHT is much more useful, as the context here is the infusion duration, and so the CSHT changes with infusion duration. CSHT is also unique for each drug/patient combination.
We can therefore say that the CSHT for:
- Fentanyl increases significantly against time
- So for fentanyl TIVA, the timing for the cessation of the fentanyl infusion is proportional to the infusion duration
- Alfentanil increases slightly against time
- The infusion should be ceased approximately 20-30 mins prior to the anticipated end
- Remifentanil is independent of infusion time
- It is easy to time the cessation of the infusion, regardless of the infusion time
This is one of the reasons why remifentanil has made TIVA much more approachable for those without extensive knowledge of the pharmacokinetics of the various opioids: There is now no need to “predict” the end of the infusion.